tbuckley/cabot-search huggingface dataset:
Abstract 5581: A genetically modified tumor-infiltrating lymphocytes product (GT202) exhibits enhanced persistence and anti-tumor efficacy against solid tumor in vivo
Authors: Jingwei Sun, Jiahui Jin, Yongchao Tan, Lingyun Chen, Quanwei Wang, Yarong Liu
Journal: Cancer Research (2022)

Abstract Adoptive cell therapy by tumor-infiltrating lymphocytes (TILs) has demonstrated significant clinical benefits for patients with solid tumors. However, the toxicities related to high-dose IL-2 that is required to support TIL survival and the exhaustion status of the final TIL product after rapid expansion in culture largely limits the clinical application and long-term efficacy of TIL therapy. Grit Biotechnology designed a genetically engineered TIL product (GT202) to express a membrane-bound cytokine that is critical for T cell activation and effector function, leading to enhanced cytotoxicity as well as persistence in vitro and in vivo. Multiple designs of the transmembrane domain of GT202 were compared and the best design was selected based on stable and efficient expression of GT202 on the membrane of TILs. GT202 demonstrated significantly increased cytotoxicity and cytokine production when cocultured with tumor cells in vitro than conventional TILs and better tumor control ability during a serial killing assay. In the meanwhile, GT202 TILs showed enhanced long-term survival and better preservation of TCR clonality without IL-2 in vitro, as well as persisted longer in multiple tissues without IL-2 over conventional TILs + IL-2 in NGS mice. Notably, GT202 TILs achieved better anti-tumor efficacy with low IL-2 in NSG mice inoculated with HLA-matched tumor cells than conventional TILs, corelated with their better infiltration and proliferation in spleen and tumor. In summary, GT202 demonstrated enhanced anti-tumor efficacy and persistence as well as decreased IL-2 dependency in vitro and in vivo. Currently, an investigator-initiated trial of GT202 is ongoing in China. Citation Format: Jingwei Sun, Jiahui Jin, Yongchao Tan, Lingyun Chen, Quanwei Wang, Yarong Liu. A genetically modified tumor-infiltrating lymphocytes product (GT202) exhibits enhanced persistence and anti-tumor efficacy against solid tumor in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5581.
Abstract LB037: Chromatin modifications guide Pax5 dependent gene expression in NE like prostate cancer
Authors: Sreyashi Bhattacharya, Ridwan Islam, Sanika Bodas, Juhi Mishra, Dipanwita Das, Kaustubh Datta, Samikshan Dutta
Journal: Cancer Research (2022)

Abstract Background: Prolonged ablation of androgen receptor pathway in prostate cancer leads to the emergence of therapy resistant neuroendocrine-like (NE-like) aggressive lineage. This NE development is associated with chromatin reprogramming underlying epigenetic alterations and changes in transcriptional network. Clinically, NE development follows a poorer progression with multifaceted therapeutic challenges. Current lack of effective understanding of this NE trans-differentiation process limits the stratification of therapeutic window with further worsened patient management. The following study aims to identify the sequential molecular players responsible for therapy resistant NE like development. Objective: The primary objective of this study is to understand how chromatin modifications along with epigenetic regulation dictates the establishment of NE trans-differentiation process in Prostate Cancer in response to Androgen Receptor blockade therapy. Methods: We generated various NE-like cell lines either by genetic modification or therapeutic selection. We performed RNA Seq, ATAC Seq and acetylated Histone (H3K18 and H3K27) ChIP Seq in our developed NE and adenocarcinoma cell lines. We next compared ATAC Seq and Acetylated histone ChIP Seq with RNA Seq in C4-2B and C4-2BER. Results: Our ATAC Seq and acetylated histone footprints (Ac H3K18 and Ac H3K27 ChIP Seq) analyses revealed an enhanced chromatin accessibility during adenocarcinoma to NE transformation. Overlapping RNA seq results further suggested newly transcribed neuronal genes with higher degrees of promoter accessibility. Transcription Factor scanning analysis among newly active gene promoters revealed preferential binding of Pax5, whose expression has been validated to be selectively occurring in NE lineage unlike adenocarcinoma. Further analysis of Pax5 promoter site suggested that changes in 5-hydroxymethylation pattern during adenocarcinoma to NE transformation guided the recruitment of PBX1 at Pax5 promoter. Validating NE patient expression in silico supported that PBX1/Pax5 expressions are selective in NE lineage development. Conclusions: Our study concludes that specific chromatin alterations guide the recruitment of PBX1 to upregulate Pax5 to maintain a therapy resistant neuronal surrounding in NE-like prostate cancer development. Citation Format: Sreyashi Bhattacharya, Ridwan Islam, Sanika Bodas, Juhi Mishra, Dipanwita Das, Kaustubh Datta, Samikshan Dutta. Chromatin modifications guide Pax5 dependent gene expression in NE like prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB037.
New Technologies Bloom Together for Bettering Cancer Drug Conjugates
Authors: Yiming Jin, Shahab Edalatian Zakeri, Raman Bahal, Andrew J. Wiemer
Journal: Pharmacological Reviews (2022)

Drug conjugates, including antibody-drug conjugates, are a step toward realizing Paul Ehrlich’s idea from over 100 years ago of a “magic bullet” for cancer treatment. Through balancing selective targeting molecules with highly potent payloads, drug conjugates can target specific tumor microenvironments and kill tumor cells. A drug conjugate consists of three parts: a targeting agent, a linker, and a payload. In some conjugates, monoclonal antibodies act as the targeting agent, but new strategies for targeting include antibody derivatives, peptides, and even small molecules. Linkers are responsible for connecting the payload to the targeting agent. Payloads impact vital cellular processes to kill tumor cells. At present, there are 12 antibody-drug conjugates on the market for different types of cancers. Research on drug conjugates is increasing year by year to solve problems encountered in conjugate design, such as tumor heterogeneity, poor circulation, low drug loading, low tumor uptake, and heterogenous expression of target antigens. This review highlights some important preclinical research on drug conjugates in recent years. We focus on three significant areas: improvement of antibody-drug conjugates, identification of new conjugate targets, and development of new types of drug conjugates, including nanotechnology. We close by highlighting the critical barriers to clinical translation and the open questions going forward. <h3>Significance Statement</h3> The development of anticancer drug conjugates is now focused in three broad areas: improvements to existing antibody drug conjugates, identification of new targets, and development of new conjugate forms. This article focuses on the exciting preclinical studies in these three areas and advances in the technology that improves preclinical development.
Abstract 926: IIKKa deletion amplifies renal transitional epithelial stem cells and initiates lethal invasive papillary urothelial cell carcinoma development
Authors: Xin Li, Feng Zhu, Chengfei Jiang, Yongmei Zhao, Bao Tran, Donna Butcher, Xiaolin Wu, Tross Debra, Yinling Hu
Journal: Cancer Research (2022)

Abstract Urothelial cell carcinoma is the most common cancer of the renal pelvis or ureter in humans. Due to a lack of animal models, its pathogenic causes remain elusive. Here, we generated IkkαΔKsp mice lacking Ikkα specifically in epithelial cells of the developing kidney and genitourinary tract as well as renal tubules. The mutant mice developed invasive papillary urothelial cell carcinomas initiated from the pelvis, leading to hydronephrosis, and the animals eventually died. Depleting neutrophils or antibiotic treatment slowed down the development of phenotypes but did not rescue them, suggesting that epithelial-cell-autonomous aberrant alterations induced by Ikkα loss are critical for the initiation of urothelial cancer. Moreover, We found that the urothelial cell carcinomas in the mutant mice highly expressed cancer stem-cell markers such as Sox2, K15, p63, Nanog, and CD44, as well as FGFR3 and osteopontin (OPN). Thus, we hypothesize that Ikkα ablation-mediated OPN and FGFR3 overexpression regulates and amplifies CD44+ renal cancer-stem cells for tumor initiation. These alterations are shared with human papillary urothelial cell carcinomas. Citation Format: Xin Li, Feng Zhu, Chengfei Jiang, Yongmei Zhao, Bao Tran, Donna Butcher, Xiaolin Wu, Tross Debra, Yinling Hu. IIKKa deletion amplifies renal transitional epithelial stem cells and initiates lethal invasive papillary urothelial cell carcinoma development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 926.
Abstract 3033: Glucose deprivation promotes lung adenocarcinoma de-differentiation due to unbalanced EZH2 activity
Authors: Pasquale Saggese, Aparamita Pandey, Eileen Fung, Giorgio Giurato, Alessandro Weisz, Steven M. Dubinett, Claudio Scafoglio
Journal: Cancer Research (2022)

Abstract Lung cancer is the most frequent cancer-related cause of death, and adenocarcinoma (LUAD) is the most frequent type. Despite the recent success of immunotherapies, survival of lung cancer patients has not significantly improved in the last decades. New therapies are necessary. We have previously identified sodium-glucose transporter 2 (SGLT2) as the major responsible for glucose uptake in LUAD, and we have showed that treatment with SGLT2 inhibitors significantly delays LUAD development and prolongs survival in murine models. However, our data shows that SGLT2 inhibitors also induce de-differentiation of LUAD cells, leading to a more aggressive phenotype and increased resistance to cisplatin. Glucose deprivation causes reduced αKG levels, leading to reduced activity of αKG-dependent histone demethylases and consequent histone hypermethylation. Supplementation of αKG or inhibition of the histone methyltransferase EZH2 reverse this phenotype, suggesting that this de-differentiated phenotype depends on insufficiency of αKG-dependent histone demethylases and unbalanced EZH2 activity. Consistently, double treatment with an SGLT2 inhibitor and an EZH2 inhibitor significantly reduces the tumor burden in a genetically engineered murine model of LUAD. We further characterized the effect of low glucose-induced tumor de-differentiation, identifying stabilization of hypoxia inducible factor 1α (HIF1α) as a major pathway responsible for the acquisition of a more aggressive phenotype following glucose deprivation. Finally, we identified an HIF1α-dependent transcriptional signature with prognostic significance in human LUAD. Our studies further our knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to nutrient deprivation and identifying novel targets to prevent the development of resistance to metabolic therapies. Citation Format: Pasquale Saggese, Aparamita Pandey, Eileen Fung, Giorgio Giurato, Alessandro Weisz, Steven M. Dubinett, Claudio Scafoglio. Glucose deprivation promotes lung adenocarcinoma de-differentiation due to unbalanced EZH2 activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3033.
Lung Cancer in Colombia
Authors: Andres Felipe Cardona, Sergio A. Mejía, Lucia Viola, Diego F. Chamorro, Leonardo Rojas, Alejandro Ruíz-Patiño, Adriana Serna, Stella Martínez, Álvaro Muñoz, July Rodríguez, Juan E. García-Robledo, Luis Eduardo Pino, Zyanya Lucia Zatarain-Barrón, Oscar Arrieta
Journal: Journal of Thoracic Oncology (2022)
Abstract 6212: Multiomics analyses reveal multimodal <i>Fusobacterium</i> DNA damage perturbations in colorectal cancer
Authors: Radhika Kataria, Jelmar Quist, Sunjae Lee, Anargyros Megalios, Elinor Sawyer, Thomas Hardiman, Chang Liu, Katherine Kelly, Theo Portlock, Saeed Shoaie, Anita Grigoriadis
Journal: Cancer Research (2022)

Abstract Fusobacterium nucleatum is an opportunistic bacterial pathogen and oncogenic microbe. To systematically investigate Fusobacterium-host interactions in colorectal cancers (CRCs), using host sequencing data, we developed a multi-omics PAThogen CHaracterization tool (PATCH) allowing for gene-level annotations. In 1,020 CRC transcriptomes and 28 genomes from The Cancer Genome Atlas (TCGA), we detected 9 Fusobacterium species and genes encoding 2,346 proteins, including carcinogenic virulence factors, oxidative stress chaperones, and immune response modulators. Fusobacterium was absent in tumor-adjacent normal tissue, however showed variable intra-tumor heterogeneity. PATCH-defined Fusobacterium-positive CRCs confirmed known and revealed novel perturbations in several host DNA damage responses (DDR) mechanisms, including deficiencies in telomere maintenance pathways, elevated cytosolic DNA/RNA sensing signaling, and mutations in genes involved in multiple oncogenic-related pathways. Moreover, PATCH uncovered Fusobacterium’s DNA integrated into the coding regions of tumor suppressor genes in the cancer genome and in non- coding regions significantly enriched in close proximity to Long Interspersed Elements (LINE-1), suggesting a potential rationale for LINE-1 hypomethylation in Fusobacterium-positive CRCs. Collectively, our analytical approaches have delineated Fusobacterium’s multimodal contribution to disrupting genomic stability, which ultimately could facilitate tailored treatment options targeting several DDR pathways in Fusobacterium-positive CRC. Citation Format: Radhika Kataria, Jelmar Quist, Sunjae Lee, Anargyros Megalios, Elinor Sawyer, Thomas Hardiman, Chang Liu, Katherine Kelly, Theo Portlock, Saeed Shoaie, Anita Grigoriadis. Multiomics analyses reveal multimodal Fusobacterium DNA damage perturbations in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6212.
Abstract 4033: A functional genome-wide screen to identify the ER degradation machinery in ER+ breast cancer cells
Authors: Zachary Sandusky
Journal: Cancer Research (2022)

Abstract Targeted protein degradation (TPD) is a new pharmaceutical strategy to hijack the ubiquitin-proteasome system to degrade target proteins. Many TPD drugs are discovered serendipitously, and we are only beginning to harness their potential. Understanding how TPD drugs co-opt the proteolysis pathway is important, as it could allow molecule re-engineering for TPD of new proteins (ie. neo-substrates). A rising example of TPD drugs are the selective estrogen receptor degraders (SERDs) - small molecule antagonists of estrogen receptor alpha (ER) that target ER protein for degradation. SERDs are the next generation of therapy for metastatic ER+ breast cancer. Currently, fulvestrant is the only FDA approved SERD, but fulvestrant is limited by poor pharmacokinetics and resistance conferred by ER mutations (ie. ER-Y537S). An intense pharmaceutical effort has developed five novel SERDs in phase three clinical trials. These novel SERDs have diverse side chains for inducing ER degradation but share advantages including non-steroidal structure, oral bioavailability, and activity against ER-Y537. Based on the diverse molecular properties of SERDs, I hypothesized they utilize different ubiquitin-proteasome pathway genes (such as E3 ligases) for ER degradation. To identify the machinery for SERD-mediated ER degradation, I designed a functional CRISPR/Cas9 screen, with highlights including a genome-wide gRNA library and measurement of endogenous ER protein in ER+ breast cancer cells. Initially focusing on genes required for fulvestrant-mediated ER degradation, we identified the proteolysis pathway as a top hit (q&amp;lt;5x10-6) including central genes in the ubiquitin-proteasome pathway (UBC, PSMA6, and NEDD8) and the ubiquitin-like SUMO pathway (UBC9 and RWDD3). Ubiquitin E3 ligases were also identified, including FBXO45 and VHL, which have been previously implicated as E3 ligases for ER. These hits were validated using inhibitors of ubiquitin-, NEDD8-, and SUMO-activating enzymes. These results demonstrate that multiple proteolysis mechanisms are sufficient for ER protein degradation. Currently, I am applying this screening approach to novel SERDs (such as elacestrant, amnecestrant, and giredestrant) to identify overlapping and unique mechanisms of degradation for wild-type ER and ER-Y537S. Importantly, understanding the mechanisms of these exciting new drugs will allow anticipation of resistance mechanisms in advanced ER+ breast cancer patients. Citation Format: Zachary Sandusky. A functional genome-wide screen to identify the ER degradation machinery in ER+ breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4033.
Abstract 5310: Physiochemical and biological characterization of anti-EGFR based bispecific antibodies in triple negative breast cancer (TNBC) models
Authors: Nishant Mohan, Xiao Luo, Yi Shen, Zachary Olson, Atul Agrawal, Yukinori Endo, David Rotstein, Lorraine Pelosof, Wen Jin Wu
Journal: Cancer Research (2022)

Abstract Triple-negative breast cancer (TNBC) accounts for approximately 10-20% of all diagnosed breast cancer. Both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) frequently overexpress in TNBC and cooperate with each other in autocrine and paracrine manner to enhance tumor growth and angiogenesis. Therapeutic mAbs targeting EGFR (cetuximab) and VEGFR2 (ramucirumab) are approved by FDA for numerous cancer indications, but none of them are approved to treat breast cancers. TNBC cells secrete VEGF-A, which mediate angiogenesis on endothelial cells in a paracrine fashion and promote cancer cell growth in autocrine manner. To disrupt autocrine/paracrine loop in TNBC models in addition to mediating anti-EGFR tumor growth signaling and anti-VEGFR2 angiogenic pathway, we generated a bispecific antibody co-targeting EGFR and VEGFR2 (designated as anti-EGFR/VEGFR2 BsAb), in which cetuximab IgG backbone is connected to the single chain variable fragment (scFv) of ramucirumab via a glycine linker. Physiochemical characterization data shows that anti-EGFR/VEGFR2 BsAb binds to both EGFR and VEGFR2 in a similar binding affinity comparable to parental antibodies. Anti-EGFR/VEGFR2 BsAb demonstrates potent in vitro and in vivo anti-tumor activity in TNBC models. Mechanistically, anti-EGFR/VEGFR2 BsAb not only directly inhibits both EGFR and VEGFR2 in TNBC cells but also disrupts autocrine mechanism in TNBC xenograft mouse model. Furthermore, anti-EGFR/VEGFR2 BsAb blocks paracrine pathway mediated by VEGF/VEGFR2 in endothelial cells. Collectively, our novel findings demonstrate that anti-EGFR/VEGFR2 BsAb inhibits tumor growth via multiple mechanisms of action and has potential to be developed as an attractive targeted therapy for TNBC. Citation Format: Nishant Mohan, Xiao Luo, Yi Shen, Zachary Olson, Atul Agrawal, Yukinori Endo, David Rotstein, Lorraine Pelosof, Wen Jin Wu. Physiochemical and biological characterization of anti-EGFR based bispecific antibodies in triple negative breast cancer (TNBC) models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5310.
Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit
Authors: François Lamontagne, Marie-Hélène Masse, Julie Menard, Sheila Sprague, Ruxandra Pinto, Daren K. Heyland, Deborah J Cook, Marie-Claude Battista, Andrew G. Day, Gordon H. Guyatt, Salmaan Kanji, Rachael Parke, Shay P. McGuinness, Bharath-Kumar Tirupakuzhi Vijayaraghavan, Djillali Annane, Dian Cohen, Yaseen M. Arabi, Brigitte Bolduc, Nicole Marinoff, Bram Rochwerg, Tina Millen, Maureen O. Meade, Lori Hand, Irene Watpool, Rebecca Porteous, Paul J. Young, Frederick D’Aragon, Emilie P. Belley-Cote, Elaine Carbonneau, France Clarke, David M. Maslove, Miranda Hunt, Michaël Chassé, Martine Lebrasseur, François Lauzier, Sangeeta Mehta, Hector Quiroz-Martinez, Oleksa G. Rewa, Emmanuel Charbonney, Andrew J.E. Seely, Demetrios J. Kutsogiannis, Remi LeBlanc, Armand Mekontso-Dessap, Tina S. Mele, Alexis F. Turgeon, Gordon Wood, Sandeep S. Kohli, Jason Shahin, Pawel Twardowski, Neill K.J. Adhikari
Journal: New England Journal of Medicine (2022)

Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction.